Process for the manufacture of pharmaceutical composition with modified release of active principle comprising the matrix

ABSTRACT

The invention relates to a process for the manufacture of a pharmaceutical composition with modified release of active principle comprising at least one active principle, a lipid matrix agent composed of ester of alcohol with at least one fatty acid and at least one adjuvant. 
     This process is characterized in that: 
     a powder composed of at least one component selected in the group comprising the active principle and the adjuvant, is mixed, while heating and fluidizing, in order to obtain individual grains; 
     the said lipid matrix agent is liquefied separately under warm conditions; 
     the said powder is then coated under warm conditions by spraying the said lipid matrix agent over the individual grains; 
     finally, the temperature of the combined product is lowered in order to allow the lipid matrix agent to solidify.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a divisional application of Ser. No. 09/269,468 filed Mar. 23,1999, now U.S. Pat. No. 6,194,005, which in turn was a national phasefiling of International Application No. PCT/FR97/01710 filed Sep. 29,1997.

The invention relates to a process for the manufacture of apharmaceutical composition with modified release of active principlecomprising a matrix.

THE PRIOR ART

“Pharmaceutical composition with modified release of active principle”denotes the pharmaceutical compositions with accelerated, sustained anddelayed release of active principle.

Various types of pharmaceutical compositions with modified release ofactive principle exist. Compositions comprising, on the one hand,uncoated granules constituting the dose of immediately available activeprinciple and, on the other hand, coated granules providing for themodified release of active principle are particularly used.

Compositions comprising a matrix effect are also used.

The invention more particularly relates to the process for manufacturingthe latter.

In this type of composition, the active principle is dispersed or coatedin a solid system, known as a matrix. The release of the activeprinciple from the matrix is achieved by contact of biological fluidswith the said matrix. More specifically, biological fluids migratethrough the matrix and dissolve the active principles and the latter arereleased by diffusion through the matrix which, simultaneously,modulates the release flow.

Hydrophilic matrices and hydrophobic matrices are distinguished.

In compositions comprising a hydrophilic matrix, the matrix is composedof an insoluble hydrophilic polymer, the concentration of which isbetween 25% and more than 50% of the weight of the composition,therefore high. This polymer is chosen from cellulose esters,carboxyvinyl esters, or acrylic or methacrylic esters. On contact withbiological fluids, the matrix becomes hydrated and swells, forming avery dense network of polymers, through which polymers the solubleactive principles diffuse. Furthermore, lipids, in particular glycerylesters, as illustrated, for example, in the document FR-B-2,573,307, canbe added in order to modulate the matrix swelling. In addition, thesecompositions include numerous adjuvants, often expensive adjuvants, athigh concentrations, which greatly increases the cost of thecomposition.

These compositions are obtained by granulation and then compression ofthe mixture formed of the polymer, active principles and variousadjuvants. These techniques often involve the use of organic solvents,which it is subsequently essential to recover in order to prevent themfrom dispersing into the atmosphere. In addition, traces of toxicsolvents can remain in the final product, which traces necessarily haveto be quantified.

In other words, the preparation of these compositions results in a highproduction cost, due to the cost of the various constituents of thecomposition, to their high proportions and to the technical constraintsto be overcome.

In the compositions comprising a hydrophobic matrix, the matrix iscomposed of a lipid matrix agent of natural origin, for examplebeeswaxes, which is highly innocuous However, its composition variesfrom one batch to another and its stability over time is not verysatisfactory.

As above, these compositions are generally obtained by granulation, by awet or solvent route, and then compression, involving high proportionsof each of the constituents.

The aim of the invention is thus to provide a novel process for themanufacture of a pharmaceutical composition with modified release ofactive principle by having the object of significantly decreasing thenumber and the proportions of each of the constituents as well as thenumber of operations, thus making it possible to obtain a formulationwhich is simple to employ and of low and reproducible cost.

DETAILED DESCRIPTION OF THE INVENTION

To overcome this combination of problems, the invention provides aprocess for the manufacture of a pharmaceutical composition withmodified release of active principle comprising at least one activeprinciple, a lipid matrix agent composed of an ester of at least onefatty acid and of alcohol, and at least one adjuvant.

This process is characterized in that:

a powder composed of at least one component selected from the groupcomprising the active principle and the adjuvant is mixed, while heatingand fluidizing, in order to obtain individual grains,

the said lipid matrix agent is liquefied separately under warmconditions,

the said powder is then coated under warm conditions by spraying thesaid lipid matrix agent over the individual grains, and, finally, thetemperature of the combined product is lowered in order to allow thelipid matrix agent to solidify.

In other words, the invention lies in the employment of a specificprocess which makes it possible to decrease the number of adjuvantsnecessary for the preparation of the composition and thus to result inan extremely simple and low-cost formula.

In addition, the process of the invention does not require anevaporation phase or a drying phase, since it does not require awet-route or solvent-route granulation step, thus making it possible tobe freed from any risk due to the presence of toxic residues in thefinal product. Furthermore, it is no longer necessary to carry out thequantitative determination of the traces of solvents, an analysis whichis very expensive.

According to the process of the invention, the praying conditions andthus the coating characteristics can be modified, in order to vary therelease profile of the active principle, by varying several parameters,the adjustment characteristics of which remain simple.

Thus, the spraying air pressure can be increased in order to promote theformation of a homogeneous film of lipid matrix agent around the grains.

Advantageously, the rate of spraying of the lipid matrix agent cansimultaneously be decreased.

In this case, an active principle release profile, that is to say apercentage of dissolution as a function of the time, is obtained whichis very low, corresponding to a slow release of the active principle.

Conversely, the spraying air pressure can be decreased in order topromote the agglomeration of the grains with one another.

Advantageously, the rate of spraying of the lipid matrix agent cansimultaneously be increased.

In this case, a release profile of the grains obtained is obtained whichis very high, corresponding to a rapid release of the active principle.

In practice and according to the mass of powder employed, the value ofthe rate of spraying of the lipid matrix agent is from two to four timeshigher when it is desired to promote the agglomeration of the grainswith one another than when it is desired to promote the formation of ahomogeneous film around the grains.

On the other hand, the value of the spraying air pressure is from one totwo times lower when it is desired to promote the agglomeration of thegrains with one another than when it is desired to promote the formationof a homogeneous film around the grains.

According to the process of the invention, it is possible, after havingdetermined a given active principle release profile, to vary the valuesof spraying air pressure and of spraying rate throughout the coatingstage, making it possible to promote the formation of a homogeneous filmaround the grains or to promote the agglomeration of the grains.

Once the sequence of the duration of the spraying air pressure and ofthe spraying rate has been determined, the coating operation can becarried out continuously and automatically.

According to another characteristic of the invention, the temperature ofthe mixture of liquefied matrix agent and of spraying air must begreater by 35° C. to 60° C. than the melting temperature of the lipidmatrix agent.

Likewise, the temperature of the fluidization air and that of the powdermust be equal to the melting temperature of the lipid matrix agent, plusor minus 10° C.

Furthermore, in order to obtain a mixture of individual grains, anair-operated fluidized bed device or a turbine device is used.

Furthermore, the lipid matrix agent can be sprayed by the air spraytechnique, that is to say liquid spraying under pressure in the presenceof compressed air.

According to a first embodiment, use is made of a powder comprising theactive principle and the adjuvant. In other words, after mixing andfluidizing the combined constituents of the powder, the lipid matrixagent is sprayed over the individual grains obtained.

When it is desired to package the product obtained in the form of asachet or hard gelatin capsule, the spraying air pressure and the rateof spraying of the lipid matrix agent are adjusted to a value whichmakes it possible to promote the formation of a homogeneous film oflipid matrix agent around the grains.

When it is desired to obtain tablets, the coated grains are subjected toa compression stage.

In an entirely surprising way, it is found that, in the case where theindividual grains are coated while promoting the formation of ahomogenous film around the said grains, whereas they exhibit a very lowrelease profile before compression, they exhibit, in contrast, a highrelease profile after compression.

Conversely, and in just as surprising a way, in the case whereagglomeration of the individual grains is promoted, whereas the saidgrains exhibit a high release profile before compression, they exhibit,in contrast, a low release profile after compression.

As already said, it thus appears highly advantageous to vary thespraying conditions throughout the coating operation in order to more orless promote the release of the active principle.

According to another embodiment of the invention, a powder composedexclusively of the active principle is used.

According to this technique, the coated grains of active principle aremixed under cold conditions with uncoated adjuvants.

Likewise, a powder composed exclusively of adjuvant(s) can be used.

In this case, the coated adjuvant grains are mixed with the uncoatedactive principle.

As above, in order to obtain tablets, the mixture obtained is subjectedto a compression stage.

The mixture obtained can be directly packaged in the form of sachets orhard gelatin capsules.

In order to avoid adhesion of the coated grains obtained, whether in thecase where all the grains are treated or whether in the case where onlya portion of the grains is treated, a stage of lubrication of the grainsis inserted between the coating stage and the stage of putting into apharmaceutical form.

Furthermore, in order to obtain greater stability of the pharmaceuticalcomposition, that is to say in order to minimize modifications relatingto the release of the active principle or principles over time, thegranules or tablets obtained can be subjected to a maturing stage in anoven, for at least 8 hours, at a temperature of between 45 and 60° C.,advantageously 55° C.

In order to solve the problem of obtaining a composition in which theproportions of constituents are low, use is made of an amount of matrixagent representing, by weight, from 1 to 15% of the final composition,advantageously from 2 to 5%.

Success is not achieved in obtaining an even coating for a value oflipid matrix agent of less than 1%.

The process becomes much less advantageous economically for a valuegreater than 15%.

These proportions are thus very low with respect to those used in theprior art, in particular in the abovementioned document FR-B-2,573,307,in which the proportions disclosed are much greater than 15% by weightof the final composition, generally 30%.

According to a first embodiment of the invention, use is made, as lipidmatrix agent, of an ester of behenic acid and of alcohol.

The alcohol is advantageously chosen from the group comprising glycerol,polyglycerol, propylene glycol, propylene glycol in combination withethylene oxide and polyethylene glycol.

These matrix agents exhibit the advantage of having a melting point ofgreater than 50° C., which prevents them from disintegrating at thecompression temperature. Furthermore, this melting point is greater thanthe internal temperature of the human body (37° C.), which allows thelipid agent to have a more pronounced matrix behaviour.

In addition, the spraying of an ester of fatty acid and of alcohol aslipid matrix agent makes it possible, in addition to the fact ofaccelerating or of slowing down the release of the active principle,furthermore to mask the taste of the starting material. This is trulyadvantageous insofar as none of the current masking techniques makes itpossible to mask the taste of the starting materials without excessivelyslowing down the release of the active principle.

Use is advantageously made of the ester of behenic acid and of glycerolexhibiting a melting point of between 69 and 74° C. and therefore muchgreater than 50° C. This ester results from the direct esterification ofbehenic acid with glycerol, to result in a mixture of glyceryl mono-,di- and tribehenate.

According to another embodiment, the lipid matrix agent is an ester ofpalmitic/stearic acid and of alcohol.

According to another characteristic of the invention, the adjuvant ischosen from hydrophobic diluting agents, hydrophilic diluting agents,binding agents or lubricating agents, alone or as a mixture.

In an advantageous embodiment, the hydrophobic diluting agent isdicalcium phosphate and the hydrophilic diluting agent is lactose.

Dicalcium phosphate exhibits the advantage of being very low in cost,which contributes to reducing the final cost of the composition.

Furthermore, the use of lactose as hydrophilic diluting agent makes itpossible to adjust the hydrophilic/lipophilic balance necessary for therelease of active principle.

In order to promote the compressibility of the grains during themanufacture of tablets, use is made of polyvinylpyrrolidone as bindingagent, which makes it possible to decrease the compressive forces of thepharmaceutical composition.

In order to avoid the adhesion of the powder to the walls of the machineduring the compressing operation, the pharmaceutical compositioncomprises a lubricating agent chosen within the group comprisingmagnesium stearate and silicone-treated talc, alone or in combination.

The silicone-treated talc is advantageously composed of 80% talc and 20%silicone oil.

The invention also relates to the composition obtained by the processdescribed above.

Nevertheless, this modified-release pharma-eutical composition can beobtained by other processes and in particular that of wet granulation,in which use is made of water as granulation solvent.

A wet granulation of the products constituting the powder is thuscarried out in a known way in order to succeed in obtaining granules,which are either introduced into capsules or agglomerated by pressing inorder to obtain tablets.

The advantages which result from the invention will emerge more clearlyfrom the following implementational examples.

FIG. 1 is a representation as a function of the time of the dissolutionprofile of batches of theophylline tablets which are prepared by theprocess of the invention.

FIG. 2 is a representation as a function of the time of the dissolutionprofile of a batch of coated granules (2A,2B) and of tablets (2C) ofacetylsalicylic acid which is manufactured according to the process ofthe invention.

FIG. 3 is a representation as a function of the time of the dissolutionprofile of a batch of coated granules (3A) and of tablets (3B) ofparacetamol which are manufactured according to the process of theinvention.

FIG. 4 is a representation as a function of the time of the dissolutionprofile of a pilot batch of ibuprofen tablets which is prepared by wetgranulation.

FIG. 5 is a representation as a function of the time of the dissolutionprofile of a batch of phenylpropanolamine and chloropheniramine tabletswhich is prepared by wet granulation.

FIG. 6 is a representation as a function of the time of the dissolutionprofile of a batch of theophylline tablets which is prepared by wetgranulation.

EXAMPLE 1

A mixture of 3 kg of powder is prepared comprising:

active principle: theophylline 1920 g hydrophobic diluting agent:dicalcium phosphate dihydrate  90 g binding agent: polyvinylpyrrolidone 90 g

Four batches of granules are prepared by the process of the inventioncomprising the following stages:

the mixture of powder obtained is sieved;

the said powder is mixed, heating while by means of an air-operatedfluidized bed, in order to obtain individual grains;

the lipid matrix agent (glyceryl behenate, sold by the Applicant Companyunder the trade name Compritol® 880 ATO) is liquefied separately at 120°C. Celsius;

the lipid matrix agent is sprayed over the heated powder mixture,

and, finally, the temperature is lowered in order to allow the lipidmatrix agent to solidify.

These stages are carried out while varying various parameters, either inorder to promote the formation of a homogeneous film around the grainsor in order to promote the agglomeration of the grains, in accordancewith the following table:

Batch Batch Batch Batch Parameters 1 2 3 4 % by weight of lipid matrixagent (Compritol ® 888 ATO) 5 4 4 5 Fluidization air flow rate (m³/h) 80110 80 80 Agglomeration Atomization air pressure (bar) 2 1.5 1.5Temperature of the powder bed 70 70 74 (° C.) Spraying rate forCompritol ® 42 40 40 (g/min) Coating Atomization air pressure (bar) 2.53.5 2 2 Temperature of the powder bed 70 66 71 70 (° C.) Spraying ratefor Compritol ® 41 20 40 40 (g/min)

The granules thus obtained are mixed in a mixer for 10 minutes with alubricant comprising 1% of magnesium stearate and 2% of silicone-treatedtalc with respect to the weight of the preparation.

In order to obtain the silicone-treated talc, a level of 20% by weightof silicone oil (dimethicone fluid 100 CST from Dow Corning) isincorporated in 80% of talc by weight.

The dissolution profile of batches of tablets obtained, after a stage ofcompression of the granules, according to the parameters of thepreceding table, comprising 100 milligrams of theophylline, has beenrepresented in FIG. 1.

Curve 1 corresponds to Batch 1.

Curve 2 corresponds to Batch 2.

Curve 3 corresponds to Batch 3.

Curve 4 corresponds to Batch 4.

These curves show that the release of active principle from the matrixis a function of the parameters of spraying air pressure and of sprayingrate of the lipid matrix agent.

As regards Batch 1, first the agglomeration of the grains is promoted bymaintaining the spraying air pressure at 2 bar and this pressure isincreased to 2.5 bar in order to promote the formation of a homogeneousfilm around the grains.

In this case, after compression, a relatively high release profile isobtained.

As regards Batch 2, the formation of a homogeneous film of lipid matrixagent around the grains is more favoured by setting the spraying airpressure at 3.5 bar and by decreasing the spraying rate.

In an entirely surprising way, after compression, a very high releaseprofile is obtained.

As regards Batches 3 and 4, the spraying air pressures are adjusted tovalues which make it possible to promote agglomeration of the grains(1.5 bar) and then the formation of the homogeneous film of lipid matrixagent around the grains (2 bar) continuously during the spraying stage.

It is very surprisingly observed that, after compression, very lowrelease profiles are obtained.

Furthermore, it is found that very good release profiles are obtained,this being achieved with very low proportions of matrix agent of theorder of 4 to 5% by weight of the final composition.

EXAMPLE 2

The process of the invention is carried out, which process consists inthat:

a powder composed of 100 grams of acetyl-salicylic acid is mixed, whileheating, by means of an air-operated fluidized bed device, in order toobtain individual grains,

3 grams of lipid matrix agent (Compritol®) are subsequently liquefiedseparately;

the acetylsalicylic acid powder is then coated by spraying the lipidmatrix agent over the individual grains;

and, finally, the temperature is lowered in order to allow the lipidmatrix agent to solidify.

Coated granules of acetylsalicylic acid are obtained, which granules aresold by the Applicant under the trade name Gattaprine.

The profile of the dissolution in acidic medium of Gattaprine, withrespect to acetylsalicylic tablets coated with ethylcellulose which aresold by Rhone-Poulenc under the trade name “Rhodine NC RP”, has beenrepresented in FIG. 2 (FIG. 2A).

The same dissolution test was carried out in basic medium in FIG. 2B.

The dissolution tests are carried out according to the method of thepharmacopoeia (USP XXIII).

The coated granules of acetylsalicylic acid obtained are subsequentlymixed with a powder consisting of:

11.25 grams of microcrystalline cellulose,

2.25 grams of talc,

1.25 grams of magnesium stearate.

The mixture obtained is subsequently subjected to a compression stage inorder to obtain microencapsulated tablets of acetylsalicylic acid.

The dissolution profile of batches of tablets of acetylsalicylic acidwhich is prepared according to the invention has been represented inFIG. 2C.

The tablets thus prepared exhibit the advantage of being devoid of anyorganic solvent and the final product therefore does not exhibit anytoxic risk. In addition, the process makes it possible to obtainproducts exhibiting good stability. This is because the lipid matrixsubstance makes it possible to protect the active principle from anyphenomenon of moisture during its storage, so that the hydrolysis of theactive principle is greatly reduced.

EXAMPLE 3

In this example, the release profile of coated paracetamol is comparedfor two different lipid matrix agents.

Example 2 is repeated, acetylsalicylic acid being replaced byparacetamol. In addition, 9 g of Compritol® are used.

The various operations are repeated, Compritol® being replaced by anester of palmitic/stearic acid and of alcohol sold by the Applicantunder the trade name “Précirol ATO 5®”. Thus, 100 g of paracetamol arecoated with 13 g of Précirol ATO 5.

The release profile of a batch of paracetamol, thus coated, has beenrepresented in FIG. 3.

It is found that the release profile of the paracetamol is higher whenPrécirol ATO 5® is used than when Compritol® is used.

As in Example 2, the coated granules of paracetamol obtained aresubsequently mixed with a powder consisting, in the same proportions, ofmicrocrystalline cellulose, of talc and of magnesium stearate and thenthe mixture obtained is subjected to a compression stage.

The release profile of the tablets thus obtained has been represented inFIG. 3B.

It is observed that, surprisingly, the release profile of the dissolvedparacetamol is higher when Compritol® is used than when Précirol ATO® isused.

EXAMPLE 4 to 6

In the examples which follow, pharmaceutical compositions with releaseof active principle are prepared by a wet granulation process.

EXAMPLE 4

One hundred grams (100 g) of granules are prepared comprising, as amixture:

active principle: ibuprofen 60 g hydrophobic diluting agent: 13 gdicalcium phosphate dihydrate hydrophilic diluting agent: 15 g lactoselipid matrix agent: 12 g qlyceryl behenate, sold by the Applicant underthe registered trade name Compritol ® 888 ATO

The granules are prepared by a wet granulation process in amixer/granulator comprising the following stages:

prior sieving of each of the constituents,

mixing the active principle and the adjuvants for five minutes,

gradual addition of 60 ml of distilled water and then mixing for 130seconds,

predrying the granules in an oven at a temperature of 45° C. for 20minutes,

screening carried out on a screening device (1.25 millimetre screen),

drying in an oven at a temperature of 45° C. for 12 hours.

The granules thus obtained are subsequently mixed in a mixer with alubricant, the composition of which is identical to that in Example 1.

In order to obtain tablets, the granules obtained are compressed with analternating compression machine well known for this application.

FIG. 4 is a representation of the dissolution profile of a pilot batch,prepared according to the invention, of tablets comprising 300 mg ofibuprofen at pH 6.8 (in vitro).

The level of lipid matrix agent was determined in order to obtain arelease profile of 90% of active principle over 12 hours.

Curve 5 corresponds to a batch which has not been subjected to amaturing operation.

Curve 6 corresponds to a batch which has been subjected to a maturingoperation in an oven for twenty-four hours at 55° C. It is found in thiscase that the degree of dissolution is markedly lower over time and isstabilized.

EXAMPLE 5

A mixture of one hundred grams (100 g) of powder is prepared comprising:

active principle: phenylpropanolamine 12.5 g active principle:chlorpheniramine 2 g hydrophobic diluting agent: 70.5 g dicalciumphosphate dihydrate lipid matrix agent: Compritol ® 888 ATO 15 g

In this example, the level of lipid matrix is determined in order toobtain a release profile of active principle which is similar to that ofthe form sold under the registered trade name Contact® of LaboratoireSmithKline Beecham.

The granules are prepared by a wet granulation process in amixer/granulator comprising the following stages:

sieving the various constituents,

mixing the active principle and Compritol® 888 ATO for five minutes,

gradual addition of 23 ml of distilled water and mixing for threeminutes,

predrying the granules in an oven at a temperature of 45° C. for 20minutes,

screening carried out on a screening device (1 millimetre screen),

drying in an oven at a temperature of 45° C. for ten hours.

The granule obtained is mixed with dicalcium phosphate in a mixer forten minutes. 1.6 g of magnesium stearate and 1.4 g of a mixture ofsilicone-treated talc similar to that in Example 1 are subsequentlyadded to 97 g of granules thus obtained.

The compression is carried out on an alternating tabletting press.

FIG. 5 is a representation of the dissolution profile of a batch oftablets, which batch is prepared according to the invention, comprising,as active principle, 75 mg of phenylpropanolamine and 12 mg ofchlorpheniramine.

Curve 7 corresponds to a batch which has not been subjected to amaturing operation.

Curve 8 corresponds to a batch which has been subjected to a maturingoperation in an oven for twenty-four hours at 55° C.

Curve 9 corresponds to a batch of tablets sold under the trade nameContact®.

It is found that the dissolution profile of the pharmaceuticalcomposition prepared according to the invention corresponds to that ofContact®.

Furthermore, the form is stabilized over time by carrying out a maturingstage.

EXAMPLE 6

A mixture of 100 g of powder is prepared comprising:

theophylline 33 g hydrophobic diluting agent: dicalcium phosphatedihydrate 49 g binding agent: polyvinylpyrrolidone 3 g lipid matrixagent: Compritol ® 888 ATO 15 g

The level of lipid matrix is determined in order to obtain a releaseprofile of 90% of active principle over 12 hours.

The granules are prepared by a wet granulation process in amixer/granulator comprising the following stages:

sieving the various constituents;

mixing the active principle and the adjuvants for 5 min;

gradual addition of 60 ml of water and mixing for 4 minutes;

predrying the granules in an oven at a temperature of 60° C. for 15 min;

screening carried out on a screening device (1.25 mm screen)

drying in an oven at a temperature of 40° C. for 3 hours.

The granules thus obtained are subsequently mixed with 2 g of magnesiumstearate and then compressed in a rotary tabletting press.

FIG. 6 is a representation of the dissolution profile of a batch oftablets, which is prepared according to the invention, comprising, asactive principle, 100 mg of theophylline.

Curve 10 corresponds to a batch which has not been subjected to amaturing operation.

Curve 11 corresponds to a batch which has been subjected to a maturingoperation in an oven for twenty-four hours at 55° C.

The process for manufacturing the composition of the invention thereforeexhibits numerous advantages.

This is because this process is characterized by the low number ofconstituents which it employs and the low proportions of each of them.

Furthermore, it makes it possible to modulate the release profile ofactive principle by varying the spraying air pressure and lipid matrixagent spraying rate conditions throughout the coating stage, thus makingit possible to promote the formation of a homogeneous film around thegrains and/or the agglomeration of the grains.

The result is a significant saving in the production cost ofmodified-release pharmaceutical compositions.

What is claimed is:
 1. A pharmaceutical composition with modifiedrelease comprising at least one active principle, optionally at leastone adjuvant, and a lipid matrix agent comprised of partial esters ofalcohol with at least one fatty acid in an amount of from about 1percent to about 15 percent, by weight, of the total pharmaceuticalcomposition wherein the pharmaceutical composition is obtained by a)mixing a powder comprised of an active principle and, optionally, anadjuvant, while heating and fluidizing, in order to obtain individualgrains; b) separately liquefying a lipid matrix agent comprised ofpartial esters of alcohol with at least one fatty-acid under warmconditions; c) then coating the powder under warm conditions by sprayingfrom 1 to 15% by weight of the final composition of the liquefied lipidmatrix agent over the individual grains, wherein the spraying airpressure, and optionally the spraying rate, are varied throughout thecoating operation so as to promote either the formation of a homogeneousfilm around the individual grains or the agglomeration of the individualgrains with one another; d) finally, decreasing the temperature of thecombined product in order to allow the lipid matrix agent to solidifyaround the grains.
 2. The pharmaceutical composition of claim 1 ,wherein the lipid matrix agent comprises either an ester of behenic acidand alcohol or an ester of palmitic/stearic acid and alcohol.
 3. Thepharmaceutical composition of claim 1 , wherein the alcohol of thepartial esters of alcohol is selected from the group consisting ofglycerol, polyglycerol, propylene glycol, propylene glycol incombination with ethylene oxide, polyethylene glycol and combinationsthereof.
 4. The pharmaceutical composition of claim 1 , wherein theactive principle is selected from the group consisting of theophylline,acetyl-salicylic acid, paracetamol, ibuprofen, phenylpropanol amine,chloropheniramine and combinations thereof.